Those who desire to develop a safe and effective microbicide continue to look toward drug delivery to provide solutions to patient compliance, drug stability and achieving effective pharmacokinetics of the multiple active agents over an acceptable duration. This proposal describes the development and testing of two new long acting vaginal drug delivery systems for the prevention of HIV in women: a thermoplastic intravaginal ring and new smart vaginal gels. We will evaluate three classes of compounds that inhibit HIV-1 1) dual reverse transcriptase/entry inhibitors (pyrimidinediones), 2) viral nucleocapid protein Zn finger inhibitors (S-acyl-mercaptobenzamido thioesters) and 3) a potent V3 loop inhibitor (G-quartet phosphothiolate backbone oligonucleotide 5TTGGGGTT3'). In specific aim 1, these compounds will subject to preformulation screening of solubility and stability alone and together. Lead members of each class will be selected based on stability and appropriateness of the compound for each drug delivery system. In specific aim 2, selected leads will be formulated in dual intravaginal ring segments made by extrusion of thermoplastic elements containing solubilized or dispersed antiviral agents. Release rate will be measured as a function of loading and ring composition. We will also optimize the mechanical properties and dimensions of the intravaginal ring to match vaginal ring products currently on the market. Based on stability and antiviral activity and toxicity results we will select two compounds form the series above and coformulate them in conjoined dual segment rings that co-deliver two antiviral agents simultaneously at concentrations customized to their pharmacokinetics and pharmacodynamics. Finally in specific aim 3, we will develop the first non-temperature sensitive smart microbicide gel out of FDA approved materials whose properties allow it to be applied at a relatively low viscosity and whose durability and duration in the vaginal lumen would increase soon after application to provide a durable and 24 hour duration gel. Two different antiviral agents from above will be formulated in these gels again based on stability, toxicity and antiviral activity collected in specific aim 1. Project 1 and 2 will interact intensely in the optimization of the gels and in the development of the pharmacokinetic models that will guide the design of the drug delivery systems. Project 3 will provide design criteria for the gels and rings from human acceptability studies.